Between the summer of 1920 and 1922, Leonell C. Strong mated an albino female mouse from his new A stock with a male from CC Little's stock of dba (dilute brown non-agouti) mice to produce the C stock. The offspring of this Cross were then selected and partially inbred, with one clear and well-defined goal: to produce inbred strains of mice which differ in susceptibility to spontaneous tumor incidence. He developed the C3H/St strain, which has an incidence of mammary carcinoma of over 90% in breeding females, and the tumor-resistant and long-lived CBA/St strain. The mammary tumor virus was isolated from C3H mice by Bittner. Mice of these two strains were distributed to other investigators at different times during their divergence. As a consequence of this, we now have at least 20 distinct substrains of C3H and CBA mice. Genetic variations between sublines of these strains have contributed to our understanding of subjects such as viral oncology, longevity, B-cell maturation, disease susceptibility, histocompatibility, and mutagenesis. Although Strong was a visionary, it is unlikely that he could have forseen what powerful immunogenetic tools his C-3H and CBA mice would become. The purpose of this review is to trace the history of Strong's C3H and CBA families of inbred strains, to review published studies showing genetic polymorphism within the C3H and CBA groups, to report on studies in our laboratory addressing genetic polymorphisms within these mouse strains, and finally, to speculate on the reasons for extensive substrain differences.